Thirteen Week Oral Toxicity Study of WR242511 in Rats. Volume 2
Abstract
This study evaluated the toxicity of WR242511 Tartrate in rats following thirteen weeks of daily oral (gavage) administration. Dose levels studied were 0 (vehicle control), 0.5, 1.5 and 4.5 mg base/kg/day. The primary treatment-related toxic effects of WR242511 were seen in the liver, lungs and RBCs. Males appeared more sensitive than females to the hepatotoxic effects of WR242511 administration. Microscopic liver lesions (hepatocyte degeneration and necrosis), and elevations in serum ALT and/or SDH levels were observed in mid and high dose males. Increased triglyceride and cholesterol levels in high dose females, and increased cholesterol levels in high dose males also suggested potential hepatocellular toxicity. Increases in total bile acids and alkaline phosphatase levels suggested hepatobiliary changes in high dose animals. Pulmonary microscopic lesions (alveolar histiocytosis) were observed in all WR242511-treated groups. These dose-related effects (hepatocyte degeneration and necrosis, and alveolar histiocytosis) probably contributed to the early deaths of seven out often high dose males. Treatment-related mild anemia was observed in mid dose and high dose animals. The lesser methemoglobinemic response seen in high dose males than in high dose females may have been secondary to the greater hepatotoxic effect in males, resulting in a reduction in the production of a direct methemoglobin-forming metabolite. Hemosiderosis in the spleen of high dose females was probably secondary to mild hemolytic anemia. Significant methemoglobin production was also observed in mid and high dose animals. Thymic lymphocyte depletion in high dose males was apparently secondary to stress produced by test article administration, but possibly could also be a direct treatment-related effect. Mild leukocytosis possibly secondary to stress and consisting of increased number of lymphocytes, neutrophils, monocytes, and/or eosinophils was seen in high dose animals and mid dose males.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 14, 1994
- Accession Number
- ADA640605
Entities
People
- Barry S. Levine
- Clyde W. Wheeler
- M. J. Tomlinson
Organizations
- University of Illinois at Chicago